Raaijmakers Jelmer, Ruth Mike M, Schildkraut Jodie A, Hombergh Erik van den, Aarnoutse Rob E, Svensson Elin M, Wertheim Heiman F L, Hoefsloot Wouter, van Ingen Jakko
Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Int J Antimicrob Agents. 2025 Feb;65(2):107423. doi: 10.1016/j.ijantimicag.2024.107423. Epub 2024 Dec 27.
Mycobacterium avium complex bacteria cause chronic pulmonary disease (MAC-PD) in susceptible patients. The recommended treatment regimen (rifampicin, ethambutol and azithromycin) achieves 65% cure rates but with considerable toxicity and drug-drug interactions [2,3]. Minocycline proved active in monotherapy experiments using the hollow-fibre model [4]. We compared the efficacy of the recommended regimen with a minocycline, ethambutol and azithromycin regimen using this model.
Epithelial lining fluid pharmacokinetic (PK) profiles of the recommended regimen and minocycline, ethambutol, azithromycin regimen were simulated. THP-1 cells infected with M. avium ATCC 700898 were exposed to these regimens for 21 d. PK profiles were determined at d 0 and d 21. The pharmacodynamic effect was measured by determining bacterial densities at d 0, 3, 7, 14 and 21 for intra- and extracellular fractions. Emergence of macrolide-resistance was monitored by inoculating azithromycin-containing agar, MIC measurements and resistance mutation analysis.
The minocycline-containing regimen exhibited a 1.5 log10 CFU/mL lower bacterial burden than the recommended regimen at d 7, though both regimens lost effectiveness over time. Treatment failure in both arms was not linked to the emergence macrolide-resistance. PK profiles simulated in the model matched those in MAC-PD patients.
Replacing rifampicin with minocycline increased the antimycobacterial activity of the MAC-PD treatment regimen in the hollow-fibre model, without jeopardizing the prevention of macrolide-resistance. This promising minocycline-containing regimen is a candidate for inclusion in clinical trials.
鸟分枝杆菌复合群细菌可导致易感患者发生慢性肺部疾病（MAC-PD）。推荐的治疗方案（利福平、乙胺丁醇和阿奇霉素）治愈率为65%，但有相当大的毒性和药物相互作用[2,3]。在使用中空纤维模型的单药治疗实验中，米诺环素被证明具有活性[4]。我们使用该模型比较了推荐方案与米诺环素、乙胺丁醇和阿奇霉素方案的疗效。
模拟推荐方案以及米诺环素、乙胺丁醇、阿奇霉素方案的上皮衬液药代动力学（PK）曲线。将感染鸟分枝杆菌ATCC 700898的THP-1细胞暴露于这些方案中21天。在第0天和第21天测定PK曲线。通过测定第0、3、7、14和21天细胞内和细胞外部分的细菌密度来测量药效学效应。通过接种含阿奇霉素的琼脂、MIC测量和耐药突变分析来监测大环内酯类耐药性的出现。
在第7天，含米诺环素的方案比推荐方案的细菌负荷低1.5 log10 CFU/mL，不过两种方案的疗效均随时间下降。两组的治疗失败均与大环内酯类耐药性的出现无关。模型中模拟的PK曲线与MAC-PD患者的曲线相符。
在中空纤维模型中，用米诺环素替代利福平可增强MAC-PD治疗方案的抗分枝杆菌活性，且不影响大环内酯类耐药性的预防。这种有前景的含米诺环素方案有望纳入临床试验。
